Hypocretin

Overview

Hypocretin, also known as orexin, is a neuropeptide that plays a crucial role in regulating arousal, wakefulness, and appetite. It is produced in the hypothalamus, a region of the brain that is involved in various physiological processes including sleep regulation, energy homeostasis, and hormone secretion.

Structure and Function

Hypocretin is composed of two peptides, hypocretin-1 and hypocretin-2, which are derived from a common precursor protein known as prepro-orexin. These peptides bind to two G-protein-coupled receptors, known as orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), to exert their physiological effects.

Hypocretin-1

Hypocretin-1, also referred to as orexin-A, is a 33-amino acid peptide with a molecular weight of approximately 3562 Da. It is highly conserved across species and is known for its role in promoting wakefulness and inhibiting REM sleep.

Hypocretin-2

Hypocretin-2, or orexin-B, is a 28-amino acid peptide with a molecular weight of approximately 2937 Da. It shares some functional similarities with hypocretin-1 but has a slightly different receptor affinity and distribution.

Physiological Roles

Hypocretin is involved in several key physiological processes:

• Sleep-Wake Regulation: Hypocretin neurons are active during wakefulness and are thought to stabilize the sleep-wake cycle by promoting arousal and inhibiting REM sleep.
• Energy Homeostasis: Hypocretin influences feeding behavior and energy expenditure, linking the regulation of sleep and metabolism.
• Reward and Addiction: Hypocretin pathways are implicated in reward processing and addiction, influencing behaviors related to drug-seeking and consumption.

Clinical Significance

Narcolepsy

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and disrupted nocturnal sleep. It is often associated with a deficiency of hypocretin-producing neurons in the hypothalamus. The loss of these neurons leads to the symptoms observed in narcolepsy, particularly in type 1 narcolepsy (narcolepsy with cataplexy).

Other Disorders

Research suggests that hypocretin may also play a role in other conditions such as insomnia, depression, and obesity, although these associations are less well understood.

Research and Therapeutic Implications

The discovery of hypocretin has led to the development of novel therapeutic approaches for sleep disorders. Orexin receptor antagonists, such as suvorexant, are used to treat insomnia by blocking the action of hypocretin and promoting sleep.

Also see

• Hypothalamus
• Narcolepsy
• Sleep-wake cycle
• Neuropeptide
• Orexin receptor